The proposed Center of Excellence in Genome Science will develop and apply novel tools for studying natural genetic variation. Following the imminent completion of reference sequences for the genomes of intensively studied organisms, a major future direction of genome research will be to analyze natural variation in genome sequences. This variation underlies genetic individuality and the evolutionary process of speciation. The proposed Center will address two major obstacles to the biological interpretation of genetic variation. First, it will develop efficient laboratory methods, based on recombinant-DNA techniques, to sequence long-targeted segments (ranging in length from 10-1000 kbp) of any genome from multiple individuals. This capability will address a major current limitation in genetic-variation research since existing technology, which is largely based on the polymerase-chain reaction, is difficult to apply even to regions the size of a typical human gene (10- 1000 kbp). Secondly, the Center will collaborate closely with leading statistical geneticists in order to couple the Center's experimental strengths to new computational methods for interpreting genetic-variation data. Although the Center's technology will be applicable to any organism, the Center's own applications will largely be to human genes. These applications are directed toward developing an improved understanding of the molecular basis of known genetic susceptibilities to type I diabetes, progressive supranuclear palsy, and neutropenia. More broadly, the Center expects, through its development of new technology and improved synergy between theory and experiment, to contribute indirectly to many research projects directed at understanding the genetic contributions to human health and disease.